Preparation of 2-substituted pyrimidines



Patented July 4, 1950 UNITED STATES PATENT OFFICE PREPARATION OF Z-SUBSTITUTED PYRIMIDIN ES Joe Haller Clark, Glenbrook, Conn., assignor to American Cyanamid Company, New York, N. Y., a corporation of Maine N Drawing. Application December 23, 1946, Serial No. 718,127

Claims. (Cl. 260-251) I 2 This invention relates to an improvement in mixed with a desired alkyl nitrile and the exthe art of preparing 2-substituted pyrimidines. cess ammonia is removed by evaporation. As a Although 2-substituted pyrimidines have been result of this reaction an alkali metal amidine prepared from unsubstituted amidines and esis formed. ters of malonic acid, the processes heretofore 5 Without isolating or otherwise purifying the available are subject to numerous disadvantages alkali metal amidine, I then add to it an ester from a commercial point of view. One such of malonic acid and a strong alkali catalyst process involved the necessity of first preparing previously dissolved in anhydrous alcohol. After an unsubstituted amidine by treatment of a the solids have been dissolved, the temperature suitable nitrile with anhydrous alcoholic hydroof the mixture is raised and the alcohol which gen chloride followed by treatment of the prodis present as solvent and which forms as a reuct with alcoholic ammonia and subsequent isosult of the reaction is distilled off. The resultlation of the amidine as the hydrochloride salt. ing alkali metal salt of the 2-substituted-4,6- Upon neutralization of the hydrochloride the dihydroxypyrimidine is then recovered and purproduct was then condensed with malonic acid ified if desired.

esters .to yield 2-substituted-4,6-dihydroxypy- It will be apparent to those in the art that rimidines. All of these operations had to be this simple method has many advantages over carried out under carefully controlled and anthe more cumbersome procedures previously hydrous conditions. available. As indicated, I may use any of the I have discovered that 2-alkyl 4,6-dihydroxyalkali metal amidines including sodium, potaspyrimidines can be prepared much more simply sium, and lithium salts. Although the preparaand under less critical reaction'conditions by tion of these alkali metal amidines has been first preparing an alkali metal salt of a desired previously described, a process preferred by me amidine and without isolation thereof reacting is shown in the specific examples which follow the alkali metal salt with an ester of malonic 26'hereinaiter. acid to yield an alkali metal salt of the corre- Also, as indicated above, the catalyst is prefsp ndin 2-substitut d-4, d hydroxypyrimidine. erab-ly an alkali metal ethoXide such as sodium This latter reaction may be illustrated by means ethoxide, potassium ethoxide and/or the alkali 0f the follow equa In the equation R metal alkoxide of other simple aliphatic alcorepresents an alkyl radical 30 hols. The reaction solvent is also preferably 0 0H 1 one of the numerous simple alcohols suchas NH RIO g methanol, ethanol, isopropanol or the like. The preferred alkali metal amidines are the 0112 CH+2110H alkyl amidines which may be easily prepared as will .be illustrated hereinafter from any suit- OK able alkyl nitrile having up to 1'7 or more carbon atoms. Dinitriles may also be used with It should be understood that the process probthe production f interesting dipyrimidine-S ably does not take place directly as shown. Uncharacterized by having an alkylene linkage at doubtedly, the reaction requires the formation 40 the 2 position such it il include Succinoof intermediate Substances and rearrangement nitrile, sebaconitrile and the like. Still other of the molecular Structure from the keto to the nitriles such as nicotinonitrile may also be used eno] formin the process.

The tajkes place in the prese'nce of a To illustrate the invention in greater particsitrong alkah Whlch acts as ecata'lytw agent ularity the following examples are given. These for example an alkali metal alkoxide a Stmhg examples illustrate preferred processes and are alkali Such as potassium hydroxideh not intended to limit the invention to any parcase the product formed would be the dlalkah t'icular reactants or reaction conditions shown. metal salt of the Z-substituted-4,6-dihydroxypyrimidine. The free 2-substituted-4,6-dihy- 5o EXAMPLE 1 droxypyrimidine is formed during the purifica- 2 n octyl 46 dihydromypy,.imidine tion process upon neutralization of the salt with an acid. 15.9 g. (0.4 atom) of potassium Although my process may start with an alkali 600 cc. (approximately) of anhydrous ammonia metal amidine as one of the intermediates, I 1g. of iron oxide (black; ferro-ferric) prefer to prepare this material in situ from more 58 g. (0.41 mole) of pelargononitrile readily available substances. To do this an alg. (140 00.; 0.88 mole) of ethyl malonate in kali metal amide is formed, as by the reaction cc. of anhydrous 23 alcohol of anhydrous ammonia and potassium or so- 12 g. (0.52 mole) of sodium in 300 cc. of anhydium metal. The alkali metal amide is then 60 drous 23 alcohol The ammonia was drawn from a tank into a dissolved. The reactionmixturewas then dis-.

tilled at atmospheric pressure until the residue was aquite sirupy-liquid.

This residue was dissolved in about 500 cc. of water and a small amount of insoluble oil removed from the solution. The solution was treated with activated charcoal, filtered and the filtrate acidified with acetic acid. The resulting precipitate was filtered and recrystallized from about. 400' cc. ofacetic acid, using charcoal. There wasobtainedin this way 3'7 g. of product which melted with decomposition at 277 (corr.) The filtrate was concentrated to about 100 cc.

. and poured into 500 cc. of ,water. The precipitated solid was filtered, digested with 350 cc. of alcohol,- filtered hot, and washed with ether. The product weighed 9 g. and decomposed at 278 (corn). The total yield of 2-n-octyl-4,6- dihydroxypyrimidine was 46 g. (50%).

EXAMPLE 2 2 n-heccyl-4,6-dihydroxypyrimidine 28.8 g. (0.735 atom) of potassium 750 cc. of ammonia 2 g. of iron oxide (black) 84 g. (0.755 mole) of enanthonitrile- 250 g. (250 00.; 1.55 moles) of ethyl malonate in 275 cc. of anhydrous 2B alcohol 23 g. (1 mole) of sodium in 350 cc. of alcohol The reaction was run as described for the n-octyl compound. There was obtained a total of 56 g. of 2 n-hexyl-4,6 dihydroxypyrimidine decomposing at 281 (corn) and 11 g. at2'79",

a total of 67 g. (45%) EXAMPLE 3 2-n-butyl-4,6-dihydroxypyrimidine 36.2 g. (0.92 atom) of potassium 1 g, of black iron oxide 750;cc. of,anhydrous ammonia (approximately) The nitrile was added at this droxypyrimidines which comprises alkyl nitrile inliquid ammonia, and

4,6-dihydroxypyrimidine;, yieldz, 8'1 g, (56%). Thedecomposition point was 3057-509. (corn) when the temperature was raised fairly rapidly.

I claim:

1. A process of preparing 2-alkyl-4=,6-dihy the steps of bringing together an alkali metal amide and an after reaction thereofremoving the excess ammonia, adding-to the'product a diester of malonic acid, an alkali metal alkoxide, and a substantially anhydrous alcohol, whereupon there is formed an alkali metal salt of a 2-a1kyl-4,6-dihydroxypyrimidine and thereafter recovering the said pyrimidine.

2. A process. of preparing, 2,-a1l yl-.4,,6- dihydroxypyrimidines which comprises the steps ofbringing together, apotassium amide andan alkylnitrile in liquid ammonia, andaften reaction, thereof removing the excess ammonia, adding, to the product a potassium salt of a 2-alkyl-4,6-dihydroxypyrimidine and thereafter recovering th said pyrimidine.

3.. A process of preparing 2-.alkyl-4,6-dihy droxypyrimidines which comprises bringing together a sodium amide and an alkyl nitrile in liquid ammonia, and thereof removing the product a diester of'malonic acid, an alkali metalv alkoxide, and a substantially anhydrous alcohol, whereupon there is formed a sodium. and

salt of 2-ally1-4,fi-dihydroxypyrimidine thereafter recovering the said pyrimidina 4. A process of preparing 2-alk yl-4,6-dihydroxypyrimidines whichcomprises the steps; of

mixing togetherv in liquid ammonia potassium amide and an alkyl nitrile and afterireaction thereof removing the excess ammonia, adding to the reaction product a diallgyl malonate, analkali metal ethoxide, and substantially anhydrous ethyl alcohol and after reaction thereof to form a' potassium salt of a 2 -alkyl substituted-4,6- dihydroxypyrimidine, recovering the said pyrimidine.

5. A process of preparing 2-alkyl-4,6-dihydroxypyrimidines which comprises mixing together, in liquid ammonia potassium amide and analkyl nitrile and after. reaction 83 g. (103 cc.; 1.0 mole) of n-valeronitrile (EK N0. 272) 29g. (1.25 atoms) of sodium in 250 cc. of 2B absolute alcohol 320 g. (2 moles) of ethyl alcohol I The reaction was run as described for 2-11- octy1-4,6-dihydroxypyrimidine. One crystallizatiOn from acetic acid gave very pure 2-n-butylmalonate in 300 cc.

thereof removing the excess ammonia, adding to the reaction product diethylmalonate, an alkali metal ethoxide, and substantially anhydrousebhyl alcohol and after reaction thereof to form a potassium salt of a 2-alkyl,substituted-4,6-dihy droxypyrimidine, recovering the said pyrimidine.

JOE HALLER CLARK;

1 REFERENCES CITED The following. references are of record in ,the.

file of this patent:

J ounAm. Chem. Soc, 44, 361-366.

Chemical Reviews, De;c.- 1945l, pages;.35,9,g 39 8,- and 399. 1

a diester of malonic acid, an alkali metal. alkoxide, and a substantially, anhydrous alcohol, whereupon there is .formed the steps of.

after reaction the, excess ammonia, adding to the steps of 

1. A PROCESS OF PREPARING 2-ALKYL-4, 6-DYHYDROXYPYRIMIDINES WHICH COMPRISES THE STEPS OF BRINGING TOGETHER AN ALKALI METAL AMIDE AND AN ALKYL NITRILE IN LIQUID AMMONIA, AND AFTER REACTION THEREOF REMOVING THE EXCESS AMMONIA, ADDING TO THE PRODUCT A DIESTER OF MALONIC ACID, AN ALKALI METAL ALKOXIDE, AND A SUBSTANTLLY ANHYDROUS ALCOHOL, WHEREUPON THERE IS FORMED AN ALKALI METAL SALT OF A 2-ALKYL-4, 6-DIHYDROXYPYRIMIDINE AND THEREAFTER RECOVERING THE SAID PYRIMIDINE. 